We continue to investigate new approaches to diagnose Cushing syndrome (CS), make the diagnosis of CS, and localize small pituitary adenomas to aid in the diagnosis and treatment of patients with CS. The results indicate that bilateral simultaneous inferior petrosal sinus (IPS) sampling distinguishes patients with ectopic ACTH secretion from those with pituitary adenomas with nearly 100% accuracy. Repeat transsphenoidal surgery is successful in eliminating the hypercortisolism of Cushing's disease in about 70% of patients. This therapy for patients with Cushing's disease after previous pituitary surgery previously had not been examined. Repeated sella exploration in the early postoperative period in patients who did not respond to the first operation was shown to be successful in most patients who received it. The subset of patients who are most likely to have success with early repeat surgery can be selected based on the findings during the first operation. MRI scanning with and without gadolinium-EDTA was used to evaluate patients with Cushing's disease preoperatively. This technique permitted identification of the adenoma in only 55% of patients with surgically-proven microadenomas. Pituitary adenomas were detected in 10% of 100 normal subjects with MRI scanning with contrast. Intraoperative ultrasound, using a prototype 12 Mhz probe developed for transsphenoidal surgery, was shown to detect and localizing very small tumors in the pituitary gland during surgery. Adenomas were detected in 70% of patients with normal sellar MRI scans. The use of these techniques resulted in curative pituitary surgery in 100% of a large group of children with Cushing's disease. Hyponatremia, which frequently occurs in the early postoperative period after pituitary surgery was shown to be produced by abnormal regulation of vasopressin secretion and abnormal excessive thirst. New advances in the ability to analyze and study pathological specimens, such as Laser capture microdissection, have opened new opportunities to study the biochemistry of pituitary adenomas. Adenoma tissue will be screened for biochemical abnormalities relating to oncogenesis and the regulation of programmed cell death. A new clinical investigation of hyperprolactinemia and prolactinomas, a disease primarily of women, is planned. The project is ideally suited for a "bench to bedside" investigation to address various clinical and biochemical aspects of these most common symptomatic secretory tumors of the pituitary.